The long-term objective of the proposed trial, International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA), is to define the role of an invasive approach in patients with stable ischemic heart disease (SIHD) and substantial ischemia. The trial hypothesis is that cardiac catheterization followed by complete revascularization plus optimal medical therapy (OMT) is superior to OMT alone as the management strategy for patients with moderate-severe ischemia on stress imaging. The primary endpoint will be time to cardiovascular death, myocardial infarction (MI), or hospitalization for unstable angina, resuscitated cardiac arrest, or heart failure. The hypothesis that the invasive strategy will improve quality of life will also be tested. Cost-effectiveness will be assessed. The COURAGE and BARI 2D trials found that an initial management strategy of coronary revascularization did not reduce the risk of death or MI compared with OMT alone in SIHD patients selected on the basis of coronary anatomy. These data raise the question whether cardiac catheterization (cath) is required in stable patients. Cath in such patients usually leads to revascularization. Although COURAGE and BARI 2D included a broad range of severity of myocardial ischemia on stress testing, most patients had mild-moderate ischemia. Observational data suggest that revascularization of patients with moderate-severe ischemia is associated with a lower likelihood of death and MI;this is not observed in patients with lesser degrees of ischemia. Only about half of patients with moderate-severe ischemia are referred for cath. It is unknown whether use rates for cath and revascularization are appropriate for optimal patient management in the era of modern medical therapy (particularly with high dose statins and antiplatelet therapy). This issue cannot be resolved using available data because prior clinical trials in SIHD have enrolled patients after cath, at which point there is substantial selection bias for enrollment based on coronary anatomy. Given the potential for improved survival and fewer cardiac events as a result of revascularization and the significant expense and risks associated with invasive management, the role of an invasive strategy is critically important to define. Defining that role is among the top 100 US priorities for comparative effectiveness research. The proposed ISCHEMIA trial will be a prospective, multicenter, international, randomized, controlled trial that will directly address the need for an invasive strategy-cath and revascularization-in patients with SIHD. A total of 8,000 patients with moderate-severe ischemia and left ventricular ejection fraction >35% will be enrolled after stress imaging from more than 400 sites. Based on the need to exclude significant left main coronary artery disease, patients who meet eligibility criteria will undergo blinded coronary CT angiography. Patients will be randomized to an invasive group that will undergo routine cath with optimal revascularization, if feasible, plus OMT or to a group that receives OMT alone. Project Narrative: This trial will inform clinicians and patients about a very common question they encounter: when a patient has a moderately to severely abnormal cardiac stress test, is it better to do an invasive angiogram (take a picture of the heart arteries) with the intention of opening or bypassing any blockages with stents or surgery plus optimal medical therapy, or is it better to optimize medical therapy and only consider the angiogram with stents or surgery if symptoms cannot be controlled? If there is a benefit to doing an angiogram and treating with stents or surgery, then clinicians and patients must be made aware of these benefits and put them into practice to prevent bad outcomes like heart attacks and death;if the results show there is no benefit from routine invasive testing, then treatment would begin with only intensive lifestyle change and medication to control symptoms and reduce risk. Either finding could provide much-needed information to guide practice and improve quality of medical care. (End of Abstract)